Monomeric and Dimeric Forms of Adiponectin Receptor Fragments and Methods of Use

ABSTRACT

Methods are disclosed for determining progression of a condition, onset of a condition, or efficacy of treatment of a condition characterized by an adipocyte imbalance in a patient. In addition, disclosed herein are methods of treating diabetes, abnormal adipocyte activity, and insulin resistance using monomeric, homodimeric, and heterodimeric forms of certain C-terminal fragments of adiponectin receptor. In addition, methods of treating abnormal adipocyte activity, treating metabolic syndrome, causing insulin secretion, increasing insulin levels, inhibiting insulin degradation enzyme, treating Alzheimer&#39;s disease, treating cardiovascular disease associated with adiponectin levels, inhibiting ADAM-17 enzyme, inhibiting a protease, treating a condition associated with TNF-alpha, and treating a condition associated with HER2-neu are disclosed. Compositions, dosage forms, and kits are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is also related to:

-   (1) U.S. application Ser. No. 10/572,882, which is the national    stage entry of PCT/EP04/10383 filed Sep. 16, 2004;-   (2) U.S. application Ser. No. 10/572,883, which is the national    stage entry of PCT/EP04/10384 filed Sep. 16, 2004;-   (3) U.S. Application No. 60/748,305 filed Dec. 7, 2005;-   (4) WO 2007/120,311 filed Dec. 4, 2006;-   (5) U.S. Application No. 60/991,328 filed Nov. 30, 2007; and-   (6) U.S. application Ser. No. 12/169,983 filed Jul. 9, 2008;    the entire disclosures of which are incorporated herein by    reference.

FIELD OF THE INVENTION

The present invention generally relates to adiponectin receptorfragments. More particularly, the invention relates to monomeric anddimeric forms of adiponectin receptor fragments, to methods of using themonomeric and dimeric forms of the adiponectin receptor fragmentsdiagnostically and therapeutically, and to compositions, dosage forms,and kits comprising the monomeric and dimeric forms of the adiponectinreceptor fragments.

BACKGROUND OF THE INVENTION

Adiponectin Receptor 1 (ADIPOR1) is a seven transmembrane G proteincoupled receptor (GPCR). See, for example, WO 01/012662 and WO01/090304. Many medically significant biological processes are mediatedby signal transduction pathways that involve G-proteins [Lefkowitz,Nature 351, 353-354 (1991)]. Certain extra cellular messengers (ECM) orC-terminal fragments (CTF), which are peptide fragments from theC-terminal of ADIPOR1 (R1 CTF) and ADIPOR2 (R2 CTF), have diagnosticvalue in human blood. Their usefulness was confirmed using a polyclonalantibody with a mass measuring SELDI-TOF immuno-affinity method. Thoseinventions are the subject of related application WO 2007/120,311, whichis incorporated herein by reference. In that work, a particular longpeptide sequence of 32 amino acids of R1 CTF was identified that wascompletely absent from all diabetic patients tested. Shorter peptidesequences were also found in blood but in both healthy and diabeticpatients. The levels of the shorter peptide sequences were generallyincreased with disease state.

It was also previously discovered that monomeric ECM32 (SEQ ID NO:1) (R1CTF32), a fragment of 3473 Da as confirmed by two separate monoclonalantibodies, when administered to patients, acted as aninsulin-sensitizing agent. That invention is the subject of copendingapplication U.S. Ser. No. 12/169,983 filed Jul. 9, 2008. As such, thisC-terminal fragment of ADIPOR1 may be a useful therapeutic agent toincrease insulin secretion in patients in need thereof, including, butnot limited to, patients suffering from diabetes, abnormal adipocyteactivity, and insulin resistance.

It has now been discovered that the dimeric forms of ECM32 and dimericforms of ECM25 are biologically active. It has also been discovered thatheterodimeric form of ECM32, or R1 CTF32 R2 CTF32 (SEQ ID NO:1 linkedvia a disulfide bond to SEQ ID NO:2), is more active than homodimericforms of ECM32 (R1 CTF32 R1 CTF32) (SEQ ID NO:1 linked via a disulfidebond to SEQ ID NO:1 or SEQ ID NO:2 linked via a disulfide bond to SEQ IDNO:2)). The methods, compositions, dosage forms, and kits of the presentinvention are directed toward these, as well as other, important ends.

SUMMARY OF THE INVENTION

It is has been unexpectedly discovered that certain dimeric forms ofC-terminal fragments of ADIPOR1 inhibit the enzymatic activity ofADAM-17 and insulin degradation enzyme (IDE) and thereby impact insulinlevels and signal peptides impacted by these enzyme such as TNF-α.Accordingly, these dimeric forms of C-terminal fragments are useful intherapeutic methods of treating diabetes, abnormal adipocyte activity,and insulin resistance. Determining the level of the dimeric forms ofthe C-terminal fragments may be used diagnostically. Usefulcompositions, dosage forms, and kits have also been discovered.

The present invention is directed, in part, to methods for determiningprogression of a condition, onset of a condition, or efficacy oftreatment of a condition characterized by an adipocyte imbalance in apatient, comprising:

determining a level of a peptide in a biological fluid sample obtainedfrom said patient;

wherein said peptide is selected from the group consisting of:

-   -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and

correlating the level with said progression of a condition, onset of acondition, or efficacy of treatment of a condition characterized by anadipocyte imbalance.

The present invention is also directed, in part, to methods of treatingdiabetes in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In other embodiments, the invention is directed to methods of treatingabnormal adipocyte activity in a patient in need thereof, comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In another embodiment, the invention is directed to methods of treatinginsulin resistance in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods oftreating metabolic syndrome in a patient in need thereof; comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofinhibiting insulin degradation enzyme (IDE) in a patient, comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In other embodiments, the invention is directed to methods of treatingAlzheimer's disease in a patient, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In other embodiments, the invention is directed to methods of treatingcardiovascular disease associated with adiponectin levels in a patient,comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofinhibiting ADAM-17 enzyme in a patient, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.        Thus, the peptides of the invention are useful as an anti-TNF        alpha therapy and as an anti-HER2 neu therapy. Anti-TNF alpha        therapy is important in treating inflammation and auto-immune        diseases, such as lupus, rheumatoid arthritis, and type-1        diabetes. Anti-HER2 neu therapy is important in impacting tumor        growth, especially in breast cancer.

In yet other embodiments, the invention is directed to methods oftreating a condition associated with TNF-alpha in a patient, comprisingthe step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods oftreating a condition associated with HER2 neu in a patient, comprisingthe step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofinhibiting a protease in a patient, comprising:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:1;    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and

wherein said protease is insulysin/insulin degradation enzyme (IDE),ADAM-17 peptidase, omptin, aureolysin, falcilysin, pepsin A, pepsin B,cathespsin D, cathepsin E, cathespsin G, cathepsin H, cathepsin L,acrocylindropepsin, acid peptidase (Cladosporium), rhodotorulapepsin,grifolisin, physarolisin, peptidase K, subtilisin aprM, subtilisin BPN′,high alkaline protease, M-peptidase sp. KSM-K16, subtilisin Carlsberg,meprinpeptidase, streptogrisin B, chymotrypsin C, peptidase Ci,camelysis, deuterolysin, aminopeptidase Apl, endothelin-convertingenzyme 1, neprilysin, leucolysisn, presenilin, thermopsin, retropepsin(human Tcell leukemia virus), bovine immunodeficiency virus retropepsin,candidapepsin SAP2, candidapepsin SAP3, candidapepsin SAP6,candiparapsin SAP1, or rhizopuspepsin, provided that said protease isnot IDE or ADAM-17 peptidase when said peptide is a monomeric peptidehaving at least about 75% identity with SEQ ID NO:1.

In yet other embodiments, the invention is directed to methods oftreating insulin resistance in a patient in need thereof, comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofcausing insulin secretion in a patient, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofincreasing insulin level in a patient, wherein said patient does notsuffer from diabetes, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In another embodiment, the invention is directed to compositions,comprising:

a peptide or a pharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and        at least one pharmaceutically-acceptable carrier.

In further embodiments, the invention is directed to compositions,comprising:

a purified peptide or a pharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and

optionally, at least one pharmaceutically-acceptable carrier.

In yet other embodiments, the invention is directed to injectable dosageforms, comprising:

the composition described herein; and

at least one solvent for said peptide.

In other embodiments, the invention is directed to inhalable dosageforms, comprising:

the composition described herein; and

at least one pharmaceutically-acceptable carrier for administration ofsaid peptide via inhalation.

In another embodiment, the invention is directed to kits, comprising:

instructions for administering an injectable dosage form to a patient;

a container comprising a composition described herein;

a container comprising a pharmaceutically-acceptable solvent for saidcompositions.

In other embodiments, the invention is directed to kits, comprising:

instructions for administering an inhalable dosage form to a patient;

a container comprising a composition described herein;

a container comprising a pharmaceutically-acceptable solvent for saidcomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a furtherunderstanding of the invention and are incorporated in and constitute apart of this specification, illustrate embodiments of the invention andtogether with the description serve to explain the principles of theinvention. In the drawings:

FIG. 1 is a plot of IDE activity as a function of the level of R2 CTF32(SEQ ID NO:2) with a two hour incubation.

FIG. 2 is a plot of TACE/ADAM-17 activity as a function of the level ofR2 CTF32 (SEQ ID NO:2) with a two hour incubation.

FIG. 3 shows the results from Example 4 of the assay for R1 CTF32 (SEQID NO:1) using the R1 CTF 32 monoclonal antibody and the R1 CTF32polyclonal antibody described in Example 2 to determine plasma levels ofR1 in diabetic and normal patients. This assay detects any forms of R1forms whether monomeric, dimeric, or bound.

FIG. 4 shows the results from Example 4 of the assay for R1 CTF32 R2CTF32 (SEQ ID NO:1 linked to SEQ ID NO:2) using the R1 CTF 32 monoclonalantibody and the R2 CTF32 polyclonal antibody described in Example 2 todetermine plasma levels of heterodimeric R1 CTF32 R2 CTF32 in diabeticand normal patients. This assay does not detect monomeric form and wouldonly detect heterodimeric form.

DETAILED DESCRIPTION OF THE INVENTION

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly indicates otherwise.

As used herein, the term “about,” when referring to a measurable valuesuch as an amount, a temporal duration, and the like, is meant toencompass variations of ±20%, preferably ±10%, more preferably ±5%, evenmore preferably ±1%, and yet even more preferably ±0.1% from thespecified value, as such variations are appropriate to perform thedisclosed methods and compositions.

As used herein, “effective amount” refers to an amount of the activeingredient as described herein that may be effective to prevent, reduceor eliminate the symptoms or condition and, with respect to thisinvention, including to treat diabetes and any other conditionsdisclosed herein that are associated with adiponectin levels, TNF-alpha,HER2 neu, to treat abnormal adipocyte activity, to treat metabolicsyndrome, to cause insulin secretion, to increase insulin levels, toinhibit insulin degradation enzyme, to treat Alzheimer's disease, totreat cardiovascular disease associated with adiponectin levels, toinhibit ADAM-17 enzyme, to treat a condition associated with TNF-alpha,and to treat a condition associated with HER2 neu. In general, theeffective amount of the ADIPO R1 fragments of the invention, ranges fromabout 0.25 mg per kg patient weight to about 200 mg per kg patientweight, preferably about 25 mg per kg patient weight to about 175 mg perkg patient weight, and more preferably about 30 mg per kg patient weightto about 150 mg per kg patient weight (and all combinations andsubcombinations therein).

As used herein, “treating” refers to the preventative, curative, andpalliative treatment of a condition, and minimally requires a palliativeeffect.

As used herein, “pharmaceutically-acceptable” refers to those compounds,materials, compositions, and/or dosage forms that are, within the scopeof sound medical judgment, suitable for contact with the tissues ofhuman beings and animals without excessive toxicity, irritation,allergic response, or other problem complications commensurate with areasonable benefit/risk ratio.

As used herein, “pharmaceutically-acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof, including acid addition salts andbase addition salts. Examples of pharmaceutically-acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The term “acid addition salt” refersto the corresponding salt derivative of a parent compound that has beenprepared by the addition of an acid. The pharmaceutically-acceptablesalts include the conventional salts or the quaternary ammonium salts ofthe parent compound formed, for example, from inorganic or organicacids. For example, such conventional salts include, but are not limitedto, those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, adipic, alginic, aspartic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,benzenesulfonic, toluenesulfonic, methanesulfonic, 2-napthalenesulfonic,ethane disulfonic, oxalic, isethionic, glucoheptanoic,glycerophosphoric, hemisulfanic, heptanoic, hexanoic, hydrochloric,hydrobromic, hydroiodic, 2-hydroxyethanesulfonic, 2-napthalenesulfonic,pectinic, phosphoric, sulfuric, 3-phenylpropionic, picric, pivalic,thiocyanic, p-toluenesulfonic, butyric, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, bisulfuric, dodecylsulfuric,ethanesulfonic, and undecanoic and the like. Thus, the term “baseaddition salt” refers to the corresponding salt derivative of a parentcompound that has been prepared by the addition of a base. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl,and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides, and others. The pharmaceutically-acceptablesalts include the conventional salts or the quaternary ammonium salts ofthe parent compound formed, for example, from inorganic or organicbases. For example, such conventional salts include, but are not limitedto, those derived from inorganic bases such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxideand ammonium hydroxide and the salts prepared from organic amines, suchas methyl amine, ethyl amine, isopropyl amine, piperidine, piperizine,pyrrolidine, ethanolamine, morpholine, diazapine, ethylene diamine,pyridine, quinoline, quinuclidine, and the like.

As used herein, “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds can also be incorporatedinto the compositions.

As used herein, “dosage unit” refers to physically discrete units suitedas unitary dosages for the particular patient to be treated. Each unitmay contain a predetermined quantity of active compound(s) calculated toproduce the desired therapeutic effect(s) in association with therequired pharmaceutical carrier. The specification for the dosage unitforms of the invention may be dictated by (a) the unique characteristicsof the active compound(s) and the particular therapeutic effect(s) to beachieved, and (b) the limitations inherent in the art of compoundingsuch active compound(s).

As used herein, “patient” refers to an animal, including a mammal,preferably a human.

As used herein, “healthy” refers to a patient that is not currentlysuffering from a condition or disease and includes a patient who ispredisposed to suffering a condition. For example, a pre-diabeticpatient would be considered a healthy patient for the purposes of thisinvention.

As used herein, “polypeptide,” “peptide,” and “protein fragment” areused interchangeably herein to refer to a polymer of amino acidresidues. The terms includes amino acid polymers in which one or moreamino acid residues is an artificial chemical mimetic of a correspondingnaturally-occurring amino acid, as well as to naturally-occurring aminoacid polymers and non-naturally-occurring amino acid polymers.

As used herein, “polynucleotide” means a polymeric form of nucleotidesof at least about 10 bases or base pairs in length, eitherribonucleotides or deoxyribonucleotides or a modified form thereof.

As used herein, “percent identity” refers the proportion of thepolypeptide sequence that matches the reference polypeptide sequence andcan be determined by comparing two optimally aligned sequences over acomparison window, wherein the polypeptide sequence in the comparisonwindow can comprise additions, deletions (i.e., gaps), derivatization,and/or conservative amino acid substitutions as compared to thereference sequence (which does not comprise additions or deletions) foroptimal alignment of the two sequences. The percentage is calculated bydetermining the number of positions at which the identical amino acidresidue occurs in both sequences to yield the number of matchedpositions, dividing the number of matched positions by the total numberof positions in the window of comparison, and multiplying the result by100 to yield the percentage of sequence identity. Identity is evaluatedusing any of the variety of sequence comparison algorithms and programsknown in the art. Such algorithms and programs include, but are by nomeans limited to, TBLASTN, BLASTP, FASTA, TFASTA, CLUSTALW, FASTDB, theentire disclosures of which are incorporated herein by reference. See,also, Pearson, et al., Proc. Natl. Acad. Sci. U.S.A., 85:2444-2448,1988; Atlschul, et al., J. Mol. Biol., 215:403410, 1990; Thompson, etal., Nucleic Acids Res., 22:4673-4680, 1994; Higgins, et al., Meth.Enzymol., 266:383402, 1996; Altschul, et al., Nature Genetics,3:266-272, 1993; Brutlag, et al., Comp. App. Biosci., 6:237-44, 1990.

As used herein, “derivatization” refers to the process of chemicallymodifying by techniques such as ubiquitination, labeling, peglyation(i.e., derivatization with polyethylene glycol), and chemical insertionor substitution of amino acids, such as ornithine, which do not normallyoccur in human proteins.

As used herein, “conservative amino acid substitution” refers to thereplacement of one amino acid with another having similar structureand/or chemical properties, such as the replacement of a leucine with anisoleucine or valine, an aspartate with a glutamate, or a threonine witha serine.

As used herein, “TACE” refers to tumor necrosis factor α-convertingenzyme, and may be used interchangeably with “ADAM-17,” which refers todisintegrin and metalloprotease domain 17, an enzyme that cleaves TNFand HERn.

As used herein, “diabetes” refers to diabetes mellitus, a chronichyperglycemia due to defective insulin secretion and/or action. TheWorld Health Organization recognizes three main forms of diabetesmellitus: type I, type II, and gestational diabetes. While all forms aredue to the beta cells of the pancreas being unable to produce sufficientinsulin to prevent hyperglycemia, the causes are different. Type Idiabetes is usually due to autoimmune destruction of the pancreatic betacells. Type II diabetes is characterized by insulin resistance in targettissues, which creates a need for abnormally high amounts of insulin anddiabetes develops when the beta cells cannot meet this demand.Gestational diabetes is similar to type II diabetes in that it involvesinsulin resistance; the hormones of pregnancy can cause insulinresistance in women genetically predisposed to developing thiscondition. Gestational diabetes typically resolves with delivery of thechild, however types I and II diabetes are chronic conditions. All typesare treatable with insulin. Type I diabetes, in which insulin is notsecreted by the pancreas, is directly treatable only with injected orinhaled insulin, although dietary and other lifestyle adjustments arepart of management. Type II may be managed with a combination of dietarytreatment, tablets and injections and, frequently, insulinsupplementation.

Normal insulin sensitivity results when insulin cause fat cells toproduce adiponectin. Adiponectin interacts with the adiponectin receptor2 in the liver and the adiponectin receptor 1 in the muscle to stopglucose production and cause glycolysis and fatty acid oxidation. Theadiponectin receptor 1 reacts with a cleaved form of adiponectin calledglobular adiponectin whereas adiponectin receptor 2 reacts to fulllength adiponectin.

Insulin resistance occurs when adipocytes become hypertropic and produceless adiponectin in response to insulin. In this state, the cells becomemore apoptotic and cell division slows. As a result, plasma adiponectinlevels decrease. Insulin levels rise in an effort to cause cells torelease more adiponectin. However, as the insulin resistance worsensmore insulin and less adiponectin is produced. The lower level ofadiponectin results in less glycolysis and fatty acid oxidation inmuscle and prevents liver glucose production from stopping. As usedherein, “insulin resistance” refers to a decrease in an individual inthe biological action of insulin in vivo as assessed by the rate ofdisposal of glucose from the bloodstream (e.g., into insulin-sensitivetissue, such as muscle, fat, and liver).

As used herein, “metabolic syndrome” or “syndrome X” refers to a clusterof risk factors that is blamed for the excess cardiovascular diseasemorbidity among overweight and obese patients and patients with type IIdiabetes mellitus. Both the World Health Organization and NationalCholesterol Education Program-Adult Treatment Patent (NCEP-ATP III) haveset forth diagnostic criteria for metabolic syndrome (Darwin Deen,American Family Physician, 69(12):2875-2882 (2004):

TABLE 1 Diagnostic Criteria for Metabolic Syndrome According to the WHOand the ATP III WHO diagnostic criteria (insulin resistance* plus two ofATP III diagnostic criteria Component the following) (three of thefollowing) Abdominal/central Waist to hip ratio: >0.90 Waistcircumference: >102 cm obesity (men), >0.85 (women), or (40 in) inmen, >88 cm (35 in) in BMI >30 kg per m² womenHypertriglyceridemia >=150 mg per dL (>=1.7 >=150 mg per dL mmol per L)Low HDL cholesterol <35 mg per dL (<0.9 mmol per <40 mg per dL (<1.036mmol L) for men, <39 mg per dL per L) for men, <50 mg per dL (<1.0 mmolper L) for women (<1.295 mmol per L) for women High bloodpressure >=140/90 mm Hg or >=130/85 mm Hg or documented use ofdocumented use of antihypertensive therapy antihypertensive therapy Highfasting glucose Impaired glucose tolerance, >=110 mg per dL (>=6.1 mmolimpaired fasting glucose, per L)† insulin resistance, or diabetesMicroalbuminuria Urinary albumin to creatinine ratio: 30 mg per g, oralbumin excretion rate: 20 mcg per minute WHO = World HealthOrganization; ATP = Adult Treatment Panel; BMI = body mass index; HDL =high-density lipoprotein. *Insulin resistance is identified by type 2diabetes mellitus or impaired fasting glucose.

As used herein, “cardiovascular disease” refers to any disease thataffects the heart and blood vessels, including diseases related toatherosclerosis (arterial disease) that can cause heart attacks andcertain types of strokes and specifically including, but not limited to,cardiovascular disease is congestive heart failure, acute myocardialinfarction, coronary artery disease, vascular blockage,arteriosclerosis, atheroscelerosis, ischemia, and combinations thereof.

As used herein, “condition associated with TNF-alpha” refers to anypathological condition or disease mediated by TNF-alpha convertingenzyme (TACE) in a mammal. Examples of such conditions and diseasesinclude, but are not limited to: HIV; hepatitis; adult respiratorydistress syndrome; bone-resorption diseases; chronic obstructivepulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis;cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamicshock; sepsis syndrome; post ischemic reperfusion injury; meningitis;psoriasis; fibrotic disease; cachexia; graft versus host disease (GVHD);graft rejection; auto-immune disease; rheumatoid spondylitis; arthriticconditions, such as rheumatoid arthritis, rheumatoid spondylitis andosteoarthritis; osteoporosis; inflammatory-bowel disease; Crohn'sdisease; ulcerative colitis; multiple sclerosis; systemic lupuserythrematosus; ENL in leprosy; radiation damage; asthma; type-1diabetes, and hyperoxic alveolar injury, and combinations thereof.Tracey, et al., 1987, Nature 330:662 664 and Hinshaw, et al., 1990,Circ. Shock 30:279 292 (endotoxic shock); Dezube, et al., 1990, Lancet,335:662 (cachexia); Millar, et al., 1989, Lancet 2:712 714 andFerrai-Baliviera, et al., 1989, Arch. Surg. 124:1400 1405 (adultrespiratory distress syndrome); Bertolini, et al., 1986, Nature 319:516518, Johnson, et al., 1989, Endocrinology 124:1424 1427, Holler, et al.,1990, Blood 75:1011 1016, and Grau, et al., 1989, N. Engl. J. Med.320:1586 1591 (bone resorption diseases); Pignet, et al., 1990, Nature,344:245 247, Bissonnette, et al., 1989, Inflammation 13:329 339 andBaughman, et al., 1990, J. Lab. Clin. Med. 115:36 42 (chronic pulmonaryinflammatory diseases); Elliot, et al., 1995, Int. J. Pharmac. 17:141145 (rheumatoid arthritis); von Dullemen, et al., 1995,Gastroenterology, 109:129 135 (Crohn's disease); Duh, et al., 1989,Proc. Nat. Acad. Sci. 86:5974 5978, Poll, et al., 1990, Proc. Nat. Acad.Sci. 87:782 785, Monto, et al., 1990, Blood 79:2670, Clouse, et al.,1989, J. Immunol. 142, 431 438, Poll, et al., 1992, AIDS Res. Hum.Retrovirus, 191 197, Poli, et al. 1990, Proc. Natl. Acad. Sci. 87:782784, Folks, et al., 1989, PNAS 86:2365 2368 (HIV and opportunisticinfections resulting from HIV).

As used herein, “condition associated with HER2-neu” refers to anypathological condition or disease mediated by human epidermal growthfactor receptor 2 (HER2-neu) in a mammal, including tumor growth,especially in breast cancer.

The nucleotide sequence of ADIPOR1 is accessible in public databases bythe accession number NM_015999 and is given in SEQ ID NO:3. The aminoacid sequence of ADIPOR1 is depicted in SEQ ID NO:4. The adiponectinreceptors, ADIPOR1 and ADIPOR2, serve as receptors for globular andfull-length adiponectin and mediate increased AMPK and PPAR-alpha ligandactivities, as well as fatty acid oxidation and glucose uptake byadiponectin [Yamauchi, et al., Nature 423: 762-769 (2003)]. Yamauchi, etal. [Yamauchi, et al., Nature 423: 762-769 (2003)] isolated cDNAsencoding ADIPOR1 and ADIPOR2 by expression cloning. The receptor ADIPOR1is published in [Yamauchi, et al., Nature 423: 762-769 (2003)].

The monomeric, homodimeric, and heterodimeric forms of the C-terminalfragments of ADIPOR1 and ADIPOR2 may be used diagnostically andtherapeutically.

In one aspect, the invention is directed to methods for determiningprogression of a condition, onset of a condition, or efficacy oftreatment of a condition characterized by an adipocyte imbalance in apatient, comprising:

determining a level of a peptide in a biological fluid sample obtainedfrom said patient;

wherein said peptide is selected from the group consisting of:

-   -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and

correlating the level with said progression of a condition, onset of acondition, or efficacy of treatment of a condition characterized by anadipocyte imbalance.

In a preferred embodiment, the level of peptide is determined using animmunoassay, especially an ELISA assay. In certain preferredembodiments, polyclonal and monoclonal antibodies, which are specificfor either the R1 CTF or R2 CTF, are employed. The following antigensequences may be used to raise antibodies that are specific in detectingeither R1 CTF or R2 CTF without cross reactivity:

SEQ ID NO: 9 (R1 CTF9): GGCTDDTLL SEQ ID NO: 10 (R2 CTF9): GGCSEEDALSEQ ID NO: 13 (RI CTF34): HFHGVSNLQEFRFMIGGGCSEEDAHVLVVAAAFVSEQ ID NO: 14 (R2 CTF34): HFYGVSNLQEFRYGLEGGCTDDTLHIFVVAGAFV

In certain embodiments of the diagnostic method, the dimeric form of thepeptide is bound to carrier protein. In other embodiments, the dimericform of the peptide is unbound.

In certain embodiments, the diagnostic method further comprisesdetermining the level of adiponectin in a biological sample obtainedfrom the subject and correlating the level of adiponectin withprogression of the condition, onset of the condition, or efficacy oftreatment of the condition.

In certain embodiments, the diagnostic method further comprisesdetermining the level of bikunin in a biological sample obtained fromthe subject and correlating the level of bikunin with progression of thecondition, onset of the condition, or efficacy of treatment of thecondition.

In certain embodiments, the diagnostic method further comprisesdetermining the level of the dimeric peptide in a biological sampleobtained from the subject and correlating the level of dimeric peptidewith progression of the condition, onset of the condition, or efficacyof treatment of the condition.

In certain embodiments, the diagnostic method further comprisesdetermining the level of white blood cells in a biological sampleobtained from the subject and correlating the level of white blood cellswith progression of the condition, onset of the condition, or efficacyof treatment of the condition.

In certain embodiments, the diagnostic method further comprisesdetermining the level of the dimeric peptide in a biological sampleobtained from the subject and correlating the level of dimeric peptidewith progression of the condition, onset of the condition, or efficacyof treatment of the condition.

In certain embodiments, the diagnostic method is for determining onsetof the condition characterized by an adipocyte imbalance. In otherembodiments, the diagnostic method is for determining progression of thecondition characterized by an adipocyte imbalance. In yet otherembodiments, the diagnostic method is for determining efficacy oftreatment of the condition characterized by an adipocyte imbalance. Incertain embodiments, the treatment is administration of a PPAR gammaagonist.

In certain embodiments of the diagnostic method, the condition ismetabolic syndrome vascular blockage, diabetes type I, diabetes type II,arteriosclerosis, cardiovascular disease (including but not limited to,congestive heart failure, acute myocardial infarction, coronary arterydisease, atherosclerosis, ischemic, or a combination thereof), insulinresistance, or a combination thereof.

The present invention provides methods for assaying for the presence orabsence and/or determining the level of the peptides of the invention inbodily fluid. The phrase “determining the level” means detecting thepresence or absence of an analyte in a sample or quantifying the amountin relative or absolute terms. A relative amount could be, for example,high, medium, or low. An absolute amount could reflect the measuredstrength of a signal or the translation of this signal strength intoanother quantitative format, such as micrograms/ml.

The monomeric, homodimeric, and heterodimeric forms of the C-terminalfragments of ADIPOR1 and ADIPOR2 useful in the methods, compositions,and kits of the invention can be detected by any suitable method.Detection paradigms that can be employed include, for example, opticalmethods, electrochemical methods (voltametry and amperometrytechniques), atomic force microscopy, and radio frequency methods, e.g.multipolar resonance spectroscopy. Optical methods include, for example,colorimetric assays, electron impedance spectroscopy, and microscope,both confocal and non-confocal. detection of fluorescence, luminescence,chemiluminescence absorbance, reflectance, transmittance. andbirefringence or refractive index, (e.g., surface plasmon resonance,ellipsometry, a resonant mirror method, a grating coupler waveguidemethod or interferometry).

In certain preferred embodiments, the level of expression, includingpresence or absence of monomeric, homodimeric, and heterodimeric formsof the C-terminal fragments of ADIPOR1 and ADIPOR2 of the invention, isassayed by an immunoassay. Those skilled in the art are aware that, inits broadest context, an “immunoassay” comprises incubating a testsample with one or more immunointeractive molecules specific for atarget for a time and under conditions sufficient for binding theretoand detecting said binding. As used herein, the term “target” refers tothe analyte that a probe is designed to bind. In certain preferredembodiments, the immunointeractive molecule will be an antibody.Conditions for incubating an antibody with a test sample vary, dependingupon the format employed in the assay, the detection methods employedand the type and nature of the antibody molecule used m the assay. Thoseskilled in the art will recognize that any one of the commonly availableimmunological assay formats, for example radioimmunoassay, enzyme-linkedimmunosorbent assays (ELISA), immuno-tubimetric, and immunonephrometric.magnetic immuno particle separation, immunochromatography,immuno-microfluidic, immuno-centrifugal, diffusion-based Ouchterlony,rocket gel immunoelectrophoresis or in situ immunoassay can be readilyadapted to the present purpose.

Immunoassays are useful in the quantification of the monomeric,homodimeric, and heterodimeric forms of the C-terminal fragments ofADIPOR1 and ADIPOR2 of the invention in a test sample, in particular todetermine whether the level of the peptides of the invention is alteredcompared to normal levels detectable in non-diseased individuals. As aconsequence, such an immunoassay is of particular use in determiningwhether a patient may have a disease or predisposition to disease. Theimmunoassay can have other uses as well, such as, for example, use inthe monitoring of disease progression or monitoring of response totherapeutic interventions. The invention described herein extends to allsuch uses of immunointeractive molecules and diagnostic assays, whichrequire said immunoassays for their performance.

By way of example only, in certain embodiments, an antibody raisedagainst the fragment is immobilized onto a solid substrate to form afirst complex and a biological test sample from a patient is broughtinto contact with the bound molecule. After a suitable period ofincubation, for a period of time sufficient to allow formation of anantibody-secondary complex, a second antibody labeled with a reportermolecule capable of producing a detectable signal is then added andincubated, allow mg sufficient time for the formation of a tertiarycomplex. Any unreacted material is washed away, and the presence of thetertiary complex is determined by observation of a signal produced bythe reporter molecule. The results can either be qualitative, by simpleobservation of the visible signal or may be quantitated by comparisonwith a control sample containing known amounts of hapten. Variations ofthis assay include a simultaneous assay, in winch both sample andlabeled antibody are added simultaneously to the bound antibody, or areverse assay in which the labeled antibody and sample to be tested arefirst combined, incubated, and then added simultaneously to the boundantibody. These techniques are well known to those skilled in the artand the possibility of variations will be readily apparent.

By “reporter molecule,” as used in the present specification, is meant amolecule which, by its chemical nature, produces an analyticallyidentifiable signal which allows the detection of antigen-boundantibody. Detection can be either qualitative or quantitative. The mostcommonly used reporter molecule in this type of assay are either coloredlatex particles, metal particles, enzymes, fluorophores or radionuclidecontaining molecules (i.e. radioisotopes).

The solid substrate is typically glass or a polymer, the most commonlyused polymers being cellulose, polyacrylamide, nylon, nitrocellulose,polystyrene, polyvinyl chloride, or polypropylene. The solid supportsmay be in the form of strips, cassettes, tubes, beads, discs ormicroplates, or any other surface suitable for conducting animmunoassay. The binding processes are well-known in the art andgenerally consist of cross-linking, covalently binding, or physicallyadsorbing the molecule to the insoluble carrier.

A variety of immunoassay formats, including, for example, competitiveand noncompetitive immunoassay formats, antigen capture assays andtwo-antibody sandwich assays can be used in the methods of the invention(Self and Cook, Curr. Opin. Biotechnol. 7:60-65 (1996)). In an antigencapture assay, antibody is bound to a solid phase, and sample is addedsuch that a monomeric, homodimeric, or heterodimeric form of theC-terminal fragments of ADIPOR1 and ADIPOR2 of the invention is bound bythe antibody. After unbound proteins are removed by washing, the amountof bound antigen can be quantitated, if desired, using, for example, aradioassay (Harfow and Lane, Antibodies A Laboratory Manual, Cold SpringHarbor Laboratory; New York. (1988)). Immunoassays can be performedunder conditions of antibody excess, or as antigen competitions, toquantitate the amount of antigen and, thus, determine a level of thepeptides of the invention.

Enzyme-linked immunosorbent assays (ELISAs) can be useful in certainmethods of the invention. In the case of an enzyme immunoassay, anenzyme is conjugated to the second antibody, generally by means ofglutaraldehyde or periodate. As will be readily recognized, however, awide variety of different conjugation techniques exist which are readilyavailable to one skilled in the art. Commonly used enzymes include, forexample, horseradish peroxidase, glucose oxidase, β-galactosidase, andalkaline phosphatase, amongst others. The substrates to be used with thespecific enzymes are generally chosen for the production, uponhydrolysis by the corresponding enzyme, of a detectable color change. Itis also possible to employ fluorogenic substrates, for example, whichyield a fluorescent product. An enzyme, such as horseradish peroxidase(HRP), alkaline phosphatase (AP), β-galactosidase, or urease, can belinked, for example, to an anti-adiponectin receptor C terminal fragmentor to a secondary antibody for use in a method of the invention. Ahorseradish-peroxidase detection system can be used, for example, withthe chromogenic substrate tetramethylbenzidine (TMB), which yields asoluble product in the presence of hydrogen peroxide that is detectableat 450 nm. Other convenient enzyme-linked systems include, for example,the alkaline phosphatase detection system, which can be used, forexample, with the chromogenic substrate p-nitrophenyl phosphate to yielda soluble product readily detectable at 405 nm. Similarly, aβ-galactosidase detection system can be used with, for example, thechromogenic substrate o-nitrophenyl-β-D-galactopyranoside (ONPG) toyield a soluble product detectable at 410 nm, or a urease detectionsystem can be used with, for example, a substrate such asurea-bromocresol purple (Sigma Immunochemicals, St. Louis, Mo.). Usefulenzyme-linked primary and secondary antibodies can be obtained from anumber of commercial sources such as Jackson Immuno-Research (WestGrove, Pa.).

In certain embodiments, the monomeric, homodimeric, and heterodimericforms of the C-terminal fragments of ADIPOR1 and ADIPOR2 of theinvention can be detected and measured using chemiluminescent detection.For example, in certain embodiments, antibodies specific for monomeric,homodimeric, and heterodimeric forms of the C-terminal fragments ofADIPOR1 and ADIPOR2 of the invention are used to capture the fragmentspresent in the biological sample and a antibody specific for thespecific antibodies and labeled with an chemiluminescent label is usedto detect the fragments present in the sample. Any chemiluminescentlabel and detection system can be used in the present methods.Chemiluminescent secondary antibodies can be obtained commercially fromvarious sources, such as Amersham. Methods of detecting chemiluminescentsecondary antibodies are known in the art and are not discussed hereinin detail.

Fluorescent detection also can be useful for detecting the peptides ofthe invention in certain methods of the invention. Useful fluorochromesinclude, for example, DAPI, fluorescein, lanthanide metals, Hoechst33258, R-phycocyanin, B-phycoerythrin, R-phycoerythrin, rhodamine, Texasred, and lissamine. Fluorescein or rhodamine labeled α2-MG-, HA-,TIMP-1- or YKL-40 specific binding agents such as anti-α2-MG, anti-HA,anti-TIMP-1, or anti-YKL-40 antibodies, or fluorescein- orrhodamine-labeled secondary antibodies can be useful in the invention.Useful fluorescent antibodies can be obtained commercially, for example,from Tago Immunologicals {Burlingame, Calif.) as described furtherbelow. Fluorescent compounds can be chemically coupled to antibodieswithout altering their binding capacity. When activated by illuminationwith light of a particular wavelength, the fluorochrome-labelledantibody adsorbs the light energy, inducing a state of excitability inthe molecule, followed by emission of the light at a characteristiccolor visually detectable with a light microscope.

Radioimmunoassays (RIAs) also can be useful in certain methods of theinvention. Such assays are well known in the art. Radioimmunoassays canbe performed, for example, with ¹²⁵I-labeled primary or secondaryantibody (Harlow and Lane, supra, 1988).

A signal from a detectable reagent can be analyzed, for example, using aspectrophotometer to detect color from a chromogenic substrate; aradiation counter to detect radiation, such as a gamma counter fordetection of ¹²⁵I, or a fluorometer to detect fluorescence in thepresence of light of a certain wavelength. Where an enzyme-linked assayis used, quantitative analysis of the amount of the monomeric,homodimeric, and heterodimeric forms of the C-terminal fragments ofADIPOR1 and ADIPOR2 of the invention can be performed using aspectrophotometer such as an EMAX Microplate Reader {Molecular Devices;Menlo Park, Calif.) in accordance with the manufacturer's instructions.The assays of the invention can be automated or performed robotically,if desired, and that the signal from multiple samples can be detectedsimultaneously.

The methods of the invention also encompass the use of capillaryelectrophoresis based immunoassays (CEIA), which can be automated, ifdesired. Immunoassays also can be used in conjunction with laser-inducedfluorescence as described, for example, in Schmalzing and Nashabeh,Electrophoresis 18:2184-93 (1997). and Bao, J. Chromatogr. B, BiomedSci. 699:463-80 (1997). Liposome immunoassays, such as flow-injectionliposome immunoassays and liposome immunosensors, also can be used todetect peptides of the invention or to determine a level of peptides ofthe invention according to certain methods of the invention (Rongen, etal., J. Immunol. Methods 204: 105-133 (1997)).

Sandwich enzyme immunoassays also can be useful in certain methods ofthe invention. In a two-antibody sandwich assay, a first antibody isbound to a solid support, and the antigen is allowed to bind to thefirst antibody. The amount of soluble C terminal adiponectin fragmentscan be quantitated by measuring the amount of a second antibody thathinds to it.

Quantitative western blotting also can be used to determine a level ofsoluble C terminal adiponectin fragments in a method of the invention.Western blots can be quantitated by well known methods such as scanningdensitometry. As an example, protein samples are electrophoresed on 10%SDS-PAGE Laemmli gels. Primary murine monoclonal antibodies are reactedwith the blot, and antibody binding confirmed to be linear using apreliminary slot blot experiment. Goat anti-mouse horseradishperoxidase-coupled antibodies (BioRad) are used as the secondaryantibody, and signal detection performed using chemi luminescence, forexample, with the Renaissance chemi luminescence kit (New EnglandNuclear: Boston, Mass.) according to the manufacturer's instructions.Autoradiographs of the blots are analyzed using a scanning densitometer(Molecular Dynamics; Sunnyvale, Calif.) and normalized to a positivecontrol. Values are reported, for example, as a ratio between the actualvalue to the positive control (densitometric index). Such methods arewell known in the art as described, for example, in Parra et al., J.Vase. Surg. 28:669-675 {1998}.

Levels of the peptides of the invention can also be determined usingprotein microarrays. Methods of producing protein microarrays that maybe adapted for detecting levels of protein in a clinical sample aredescribed in the art (see for example of Xiao, et al., (2005) Mol. CellEndocrinol.; 230(1-2):95-10; Protein Microarrays (2004) Mark Schena (Ed)Jones & Bartlett Publishers, Inc.). U.S. Patent Publication 2003/0153013describes methods of defecting proteins, e.g. antigens or antibodies, byimmobilizing antibodies in a protein microarray on a membrane andcontacting the microarray with detection proteins that can bind to theproteins to form protein complexes. Similarly, U.S. Patent Publication2004/0038428 describes methods of constructing protein microarrays.

In certain preferred embodiments, a sample is analyzed by means of abiochip. Biochips generally comprise solid substrates and have agenerally planar surface, to which a capture reagent (also called anadsorbent or affinity reagent) is attached. Frequently, the surface of abiochip comprises a plurality of addressable locations, each of whichhas the capture reagent bound there.

Protein biochips are biochips adapted for the capture of peptides. Manyprotein biochips are described in the art. These include, for example,protein biochips produced by Ciphergen Biosystems, Inc. (Fremont,Calif.), Packard BioScience Company (Meriden, Conn.). Zyomyx (Hayward,Calif.), Phylos (Lexington, Mass.), and Biacore (Uppsala, Sweden).Examples of such protein biochips are described in the following patentsor published patent applications: U.S. Pat. No. 6,225,047, WO 99/51773,U.S. Pat. No. 6,329,209, WO 00/56934 and U.S. Pat. No. 5,242,828,incorporated herein by reference in their entirety and for all purposes.

For use herein, the assay methods can involve capturing the peptides ofthe invention onto a solid substrate. Typically they will be capturedusing a biospecific capture reagent such as an antibody and, mparticular, an antibody used in an immunoassay. Biospecific capturereagents include those molecules that bind a target analyte with anaffinity of, for example, at least 10⁻⁹ M, 10⁻¹⁰ M, 10⁻¹¹ M, or 10⁻¹²M.These molecules also can be captured with non-specific methods, such aschromatographic materials.

In certain embodiments of the present invention, the peptides of theinvention will be detected by mass spectrometry. Examples of massspectrometers are time-of-flight magnetic sector, quadrupole filter, iontrap, ion cyclotron resonance, electrostatic sector analyzer, andhybrids of these.

A preferred mass spectrometric technique for use in the invention is“Surface Enhanced Laser Desorption and Ionization” or “SELDI,” asdescribed, for example, in U.S. Pat. No. 5,719,060 and U.S. Pat. No.6,225,047, each of which is incorporated herein by reference in itsentirety and for all purposes. This refers to a method ofdesorption/ionization gas phase ion spectrometry (e.g. laserdesorption/ionization mass spectrometry) in which an analyte is capturedon the surface of a SELDI probe that engages the probe interface of themass spectrometer.

One version of SELDI is called “affinity mass spectrometry.” Thisversion involves the use of probes comprising of an absorbent surface(an “affinity mass spectrometry probe”). In this context, “probe” refersto a device adapted to engage a probe interface and to present ananalyte to ionizing energy for ionization and introduction into a massspectrometer. A probe typically includes a solid substrate, eitherflexible or rigid, that has a sample-presenting surface, on which ananalyte is presented to the source of ionizing energy.

Another version of SELDI is Surface-Enhanced Neat Desorption (“SEND”),which involves the use of probes comprising energy absorbing moleculesattached to the probe surface (“SEND probe”). The phrase “Energyabsorbing molecules” (EAM) denotes molecules that are capable ofabsorbing energy from a laser desorption/ionization source and,thereafter, contributing to desorption and ionization of analytemolecules in contact therewith. The EAM category includes molecules usedin MALDI frequently referred to as “matrix,” and is exemplified bycinnamic acid derivatives, sinapinic acid (SPA), cyano-hydroxy-cinnamicacid (CHCA) and dihydroxybenzoic acid, ferulic acid, andhydroxyaceto-phenone derivatives. In certain embodiments, theenergy-absorbing molecule is incorporated into a linear or cross-linkedpolymer, e.g., a polymethacrylate. For example, the composition can be aco-polymer of a-cyano-4-methacryloyloxycinnamic acid and acrylate. Inanother embodiment, the composition is a co-polymer ofa-cyano-4-methacrylyloylcinnamic acid, acrylate, and3-(tri-ethoxy)silylpropyl methacrylate. In another embodiment, thecomposition is a co-polymer of a-cyano-4-methacryoyloxycinnamic acid andoctadecylmethacrylate (“C18 SEND”). SEND is further described in U.S.Pat. No. 6,124,137, incorporated herein by reference in its entirety andfor all purposes.

A “selective surface” can be used to capture the fragments for SELDIanalysis. The selective surface has an “adsorbent,” also called a“binding moiety” or “capture reagent” attached to the surface. An“adsorbent” or “capture reagent” or “binding moiety,” can be anymaterial capable of binding an analyte. The capture reagent can beattached directly to the substrate of the selective surface, or thesubstrate can be a “reactive surface” that carries a “reactive moiety”that is capable of binding the capture reagent, e.g. through a reactionforming a covalent or coordinate covalent bond. Epoxide andcarbodiimidazole are useful reactive moieties to covalently bindpolypeptide capture reagents such as antibodies or cellular receptors.Nitriloacetic acid and iminodiacetic acid are useful reactive moietiesthat function as chelating agents to bind metal ions that interactnon-covalently with histidine containing peptides.

In certain embodiments, the adsorbent used to capture the peptides ofthe invention comprises a biospecific capture reagent. A “biospecificadsorbent” refers to an adsorbent that binds to an analyte with anaffinity of at least 10⁻⁹ M, 10⁻¹⁰ M, 10⁻¹¹ M, or 10⁻¹²M. The preferredbiospecific capture reagent is an antibody or a binding fragmentthereof. This includes intact immunoglobulins and the variants aridportions of them well known in the art such as. Fab′ fragments, F(ab)′2fragments, and scFv proteins. Other biospecific capture reagents includeaffibodies (Affibody, Teknikringen 30, floor 6, Box 700 04. StockholmSE, 10044, Sweden, U.S. Pat. No. 5,831,012; see also Surface Logix,Inc., 50 Soldiers Held Place, Brighton, Mass. 02135 and Hodneland, C. D,et al., 2002, Proc Natl. Acad. Sci. 99: 5048-5052).

The fragments of the present invention can be captured onchromatographic adsorbents. “Chromatographic adsorbent” refers to anadsorbent material typically used in chromatography. Chromatographicadsorbents include, for example, nitrocellulose membranes, ion exchangematerials, metal chelators (e.g., nitriloacetic acid or iminodiaceticacid), immobilized metal chelates, hydrophobic interaction adsorbents,hydrophilic interaction adsorbents, dyes, simple biomolecules (e.g.,nucleotides, amino acids, simple sugars and fatty acids) and mixed modeadsorbents (e.g., hydrophobic attraction/electrostatic repulsionadsorbents).

In certain embodiments, a substrate with an adsorbent is contacted withthe sample, e.g., patient serum, for a period of time sufficient toallow the target analytes that may be present to bind to the adsorbent.After an incubation period, the substrate is washed to remove unboundmaterial. Any suitable washing solutions can be used; preferably,aqueous solutions are employed. The extent to which molecules remainbound can be manipulated by adjusting the stringency of the wash. Theelution characteristics of a wash solution can depend, for example, onpH, ionic strength, hydrophobicity, degree of chaotropism, detergentstrength, and temperature. Unless the probe has both SEAC and SENDproperties, an energy absorbing molecule then is applied to thesubstrate with the bound target analytes.

The biomolecules bound to the substrates can be detected in a gas phaseion spectrometer such as a time-of-flight mass spectrometer. The targetanalytes can be ionized by an ionization source such as a laser, thegenerated ions are collected by an ion optic assembly, and then a massanalyzer disperses and analyzes the passing ions. The detector thentranslates information of the detected ions into mass-to-charge ratios.Detection of a target analyte typically will involve detection of signalintensity. Thus, both the quantity and mass of the target analyte can bedetermined.

In another mass spectrometry method, the target analytes can be firstcaptured on a chromatographic resin having chromatographic propertiesthat bind the target analytes, e.g., an antibody or antibodies, in thepresent example, this can include an immuno-chromatographic resin thatcomprises antibodies that bind C-terminal adiponectin receptorfragments. Unbound material can be washed from the resin. Then thetarget analytes can be eluted from the resin. Finally, the eluted targetanalytes can be detected by MALDI or by SELDI.

Analysis of analytes by time-of-flight mass spectrometry generates atime-of-flight spectrum. The time-of-flight spectrum ultimately analyzedtypically does not represent the signal from a single pulse of ionizingenergy against a sample, but rather the sum of signals from a number ofpulses This reduces noise and increases dynamic range. Thistime-of-flight data is then subject to data processing.

Data generated by desorption and detection of target analytes can beanalyzed with the use of a programmable digital computer. The computerprogram analyzes the data Io indicate the number of proteins detected,aid optionally the strength of the signal and the determined molecularmass for each target analyte detected. Data analysis can include stepsof determining signal strength of a target analyte and removing datadeviating from a predetermined statistical distribution. For example,the observed peaks can be normalized, by calculating the height of eachpeak relative to some reference. The reference can be background noisegenerated by the instrument and chemicals such as the energy absorbingmolecule, which is set as zero in the scale.

Analysis generally involves the identification of peals in the spectrumthat represent signal from an analyte. Peak selection can be donevisually, but software is available that can automate the detection ofpeaks. In general, this software functions by identify signals having asignal-lo-noise ratio above a selected threshold and labeling the massof the peak at the centroid of the peak signal. In one usefulapplication, many spectra are compared to identify identical peakspresent in some selected percentage of the mass spectra. One version ofthis software clusters all peaks appearing in the various spectra withina defined mass range, and assigns a mass (M/Z) to all the peaks that arenear the mid-point of the mass (M/Z) cluster.

Software used to analyze the data can include code that applies analgorithm to the analysis of the signal to determine whether the signalrepresents a peak in a signal that corresponds to a large, analyteaccording to the present invention. The software also can subject thedata regarding observed target analyte peaks to classification tree orANN analysis, to determine whether a target analyte peak or combinationof target analyte peaks is present that indicates cardiovascular diseasestatus. Analysis of the data may be “keyed” to a variety of parametersthat are obtained, either directly or indirectly, from the massspectrometric analysis of the sample. These parameters include, but arenot limited to, the presence or absence of one or more peaks, the shapeof a peak or group of peaks, the height of one or more peaks, the log ofthe height of one or more peaks, and other arithmetic manipulations ofpeak height data.

This invention further provides antibodies that specifically bind to theC-terminal fragments of the adiponectin receptor. Methods of makingantibodies having binding specificity to select peptides are well knownin the art. For example, such antibodies can be selected by immunizingan animal with the target molecule, generating antibodies, and testingthe antibodies to identify whether a particular antibody binds with thetarget molecule. Antibodies that bind with the target molecule can beselected. For example, one can generate monoclonal antibodies againstthese molecules.

The phrase “specifically binds to” refers to a binding reaction which isdeterminative of the presence of a target in the presence of aheterogeneous population of other biologics. Thus, under designatedassay conditions, the specified binding region bind preferentially to aparticular target and do not bind in a significant amount to othercomponents present in a test sample. Specific binding to a target undersuch conditions can require a binding moiety that is selected for itsspecificity for a particular target. A variety of assay formats can beused to select binding regions that are specifically reactive with aparticular analyte. Typically a specific or selective reaction will beat least twice background signal or noise and more typically more than10 times background.

The term “antibody” is used in the broadest sense and specificallycovers monoclonal antibodies, polyclonal antibodies, antibodycompositions with polyepitopic specificity, bispecific antibodies,diabodies, chimeric, single-chain, and humanized antibodies, as well asantibody fragments (e.g., Fab, F(ab′)₂, and Fv), so long as they exhibitthe desired biological activity. Antibodies can be labeled for use inbiological assays (e.g., radioisotope labels, fluorescent labels) to aidin detection of the antibody.

Antibodies can be labeled/conjugated to reporter molecules for use inbiological assays (e.g., radioisotope labels, fluorescent labels) to aidin detection of the fragments described herein.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that can be present inminor amounts. Monoclonal antibodies are highly specific, being directedagainst a single antigenic site. Furthermore, in contrast toconventional (polyclonal) antibody preparations which typically includedifferent antibodies directed against different determinants (epitopes),each monoclonal antibody is directed against a single determinant on theantigen. In addition to their specificity, the monoclonal antibodies areadvantageous in that they are synthesized by the hybridoma culture,uncontaminated by other immunoglobulins. The modifier “monoclonal”indicates the character of the antibody as being obtained from asubstantially homogeneous population of antibodies, and is not to beconstrued as requiring production of the antibody by any particularmethod. For example, the monoclonal antibodies to be used in accordancewith the present invention can be made by the hybridoma method firstdescribed by Kohler, et al., Nature, 256: 495, 1975, or can be made byrecombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567, Cabilly, etal.). The “monoclonal antibodies” can also be isolated from phageantibody libraries using the techniques described in Clackson, et al.,624-628, 1991; Marks, et al., J. Mol. Biol., 222: 581-597, 1991, forexample.

The monoclonal antibodies herein specifically include “chimeric”antibodies (immunoglobulins) in which a portion of the heavy and/orlight chain is identical with or homologous to corresponding sequencesin antibodies derived from a particular species or belonging to aparticular antibody class or subclass, while the remainder of thechain(s) is identical with or homologous to corresponding sequences inantibodies derived from another species or belonging to another antibodyclass or subclass, as well as fragments of such antibodies, so long asthey exhibit the desired biological activity (Cabilly, et al., supra;Morrison, et al., Proc. Natl. Acad. Sci. U.S.A., 81: 6851-6855, 1984).

Monoclonal antibodies can be obtained by various techniques familiar tothose skilled in the art. Briefly, spleen cells from an animal immunizedwith a desired antigen are immortalized, commonly by fusion with amyeloma cell (see, Kohler, et al., Eur. J. Immunol., 6: 511-519, 1976).Alternative methods of immortalization include transformation withEpstein Barr Virus, oncogenes, or retroviruses, or other methods wellknown in the art. Colonies arising from single immortalized cells arescreened for production of antibodies of the desired specificity andaffinity for the antigen, and yield of the monoclonal antibodiesproduced by such cells can be enhanced by various techniques, includinginjection into the peritoneal cavity of a vertebrate host.Alternatively, one can isolate DNA sequences which encode a monoclonalantibody or a binding fragment thereof by screening a DNA library fromhuman B cells according to the general protocol outlined by Huse, etal., Science, 246: 1275-1281, 1989.

Monoclonal antibodies and polyclonal sera can be collected and titeredagainst the immunogen protein in an immunoassay, for example, a solidphase immunoassay with the immunogen immobilized on a solid support.Typically, polyclonal antisera with a titer of 10⁴ or greater areselected and tested for their cross reactivity against, using acompetitive binding immunoassay. Specific polyclonal antisera andmonoclonal antibodies will usually bind with a K_(d) of at least about0.1 mM, more usually at least about 1 μM, preferably at least about 0.1μM or better, and most preferably, 0.01 μM or better.

“Humanized” forms of non-human (e.g., murine) antibodies are chimericimmunoglobulins, immunoglobulin chains or fragments thereof (such as Fv,Fab, Fab′, F(ab′)₂ or other antigen-binding subsequences of antibodies)which contain minimal sequence derived from non-human immunoglobulin.For the most part, humanized antibodies are human immunoglobulins(recipient antibody) in which residues from a complementary-determiningregion (CDR) of the recipient are replaced by residues from a CDR of anon-human species (donor antibody) such as mouse, rat or rabbit havingthe desired specificity, affinity, and capacity. In some instances, Fvframework region (FR) residues of the human immunoglobulin are replacedby corresponding non-human residues. Furthermore, humanized antibodiescan comprise residues which are found neither in the recipient antibodynor in the imported CDR or framework sequences. These modifications aremade to further refine and optimize antibody performance. In general,the humanized antibody will comprise substantially all of at least one,and typically two, variable domains, in which all or substantially allof the CDR regions correspond to those of a non-human immunoglobulin andall or substantially all of the FR regions are those of a humanimmunoglobulin sequence. The humanized antibody optimally also willcomprise at least a portion of an immunoglobulin constant region (Fc),typically that of a human immunoglobulin. For further details, seeJones, et al., Nature, 321: 522-525, 1986; Reichmann, et al., Nature,332: 323-329, 1988; Presta, Curr. Op. Struct. Biol., 2: 593-596, 1992.The humanized antibody includes a Primatized™ antibody wherein theantigen-binding region of the antibody is derived from an antibodyproduced by immunizing macaque monkeys with the antigen of interest.

A number of immunogens comprising portions of the fragments describedherein can be used to produce antibodies specifically reactive with thefragments. For example, a fragment of the present invention, can beisolated using techniques known in the art. Recombinant protein can beexpressed in eukaryotic or prokaryotic cells as described above, andpurified as generally described above. Recombinant protein is thepreferred immunogen for the production of monoclonal or polyclonalantibodies. Alternatively, a synthetic peptide derived from thesequences disclosed herein and conjugated to a carrier protein can beused an immunogen. Naturally occurring protein can also be used eitherin pure or impure form. The product is then injected into an animalcapable of producing antibodies. Either monoclonal or polyclonalantibodies can be generated, for subsequent use in immunoassays tomeasure the protein.

Methods of production of polyclonal antibodies are known to those ofskill in the art. An inbred strain of mice (e.g., BALB/C mice) orrabbits is immunized with the protein using a standard adjuvant, such asFreund's adjuvant, and a standard immunization protocol. The animal'simmune response to the immunogen preparation is monitored by taking testbleeds and determining the titer of reactivity to the beta subunits.When appropriately high titers of antibody to the immunogen areobtained, blood is collected from the animal and antisera are prepared.Further fractionation of the antisera to enrich for antibodies reactiveto the protein can be done if desired (see, Harlow & Lane, supra).

In a further embodiment, antibodies or antibody fragments can beisolated from antibody phage libraries generated using the techniquesdescribed in McCafferty, et al., Nature, 348: 552-554, 1990; Clackson,et al., Nature, 352: 624-628, 1991; Marks, et al., J. Mot. Biol., 222:581-597, 1991, describe the isolation of murine and human antibodies,respectively, using phage libraries. Subsequent publications describethe production of high affinity (nM range) human antibodies by chainshuffling (Mark, et al., Bio/Technology, 10: 779-783, 1992), as well ascombinatorial infection and in vivo recombination as a strategy forconstructing very large phage libraries (Waterhouse, et al., Nuc. Acids.Res., 21: 2265-2266, 1993). Thus, these techniques are viablealternatives to traditional monoclonal antibody hybridoma techniques forisolation of monoclonal antibodies.

In certain embodiments, the antibodies are selected to distinguishbetween one fragment of C-terminal adiponectin receptor and another,that is, the antibodies are selected that specifically bind to one form,but not another, under the same assay conditions.

Accordingly, the present invention provides an antibody thatspecifically binds to an epitope of an adiponectin receptor fragmenthaving SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:6.

In certain embodiments, the condition is metabolic syndrome, diabetes(including type I diabetes, type II diabetes, and gestational diabetes),cardiovascular disease (including congestive heart failure, acutemyocardial infarction, coronary artery disease, vascular blockage,arteriosclerosis, atheroscelerosis, ischemia, or combinations thereof),insulin resistance, and Alzheimer's disease.

Accordingly, the present invention is directed, in part, to methods oftreating diabetes in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In other embodiments, the invention is directed to methods of treatingabnormal adipocyte activity in a patient in need thereof, comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In another embodiment, the invention is directed to methods of treatinginsulin resistance in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods oftreating metabolic syndrome in a patient in need thereof; comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In certain embodiments of the invention, the patient suffers from type Ior type II diabetes. In other embodiments of the invention, patientsuffers from gestational diabetes.

In yet other embodiments, the invention is directed to methods ofinhibiting insulin degradation enzyme (IDE) in a patient, comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In other embodiments, the invention is directed to methods of treatingAlzheimer's disease in a patient, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;

a sixth heterodimer comprising a first mer unit and a second mer unit,wherein said first mer unit has at least about 75% identity with SEQ IDNO:2 and wherein said second mer unit has at least about 75% identitywith SEQ ID NO:6, and wherein said first mer unit and said second merunit are linked via a disulfide bond;

-   -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In other embodiments, the invention is directed to methods of treatingcardiovascular disease associated with adiponectin levels in a patient,comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofinhibiting ADAM-17 enzyme in a patient, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.        Thus, peptides of the invention are useful as an anti-TNF alpha        therapy and as an anti-HER2 neu therapy. Anti-TNF alpha therapy        is important in treating inflammation and auto-immune diseases,        such as lupus, rheumatoid arthritis, and type-1 diabetes.        Anti-HER2 neu therapy is important in impacting tumor growth,        especially in breast cancer.

In yet other embodiments, the invention is directed to methods oftreating a condition associated with TNF-alpha in a patient, comprisingthe step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods oftreating a condition associated with HER2 neu in a patient, comprisingthe step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofinhibiting a protease in a patient, comprising:

-   -   administering to said patient an effective amount of a peptide        or a pharmaceutically-acceptable salt thereof;    -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:1;    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and

wherein said protease is insulysin/insulin degradation enzyme (IDE),ADAM-17 peptidase, omptin, aurcolysin, falcilysin, pepsin A, pepsin B,cathespsin D, cathepsin E, cathespsin G, cathepsin H, cathepsin L,acrocylindropepsin, acid peptidase (Cladosporium), rhodotorulapepsin,grifolisin, physarolisin, peptidase K, subtilisin aprM, subtilisin BPN′,high alkaline protease, M-peptidase sp. KSM-K16, subtilisin Carlsberg,meprinpeptidase, streptogrisin B, chymotrypsin C, peptidase Ci,camelysis, deuterolysin, aminopeptidase Apl, endothelin-convertingenzyme 1, neprilysin, leucolysisn, presenilin, thermopsin, retropepsin(human Tcell leukemia virus), bovine immunodeficiency virus retropepsin,candidapepsin SAP2, candidapepsin SAP3, candidapepsin SAP6,candiparapsin SAP1, or rhizopuspepsin, provided that said protease isnot IDE or ADAM-17 peptidase when said peptide is a monomeric peptidehaving at least about 75% identity with SEQ ID NO:1.

In yet other embodiments, the invention is directed to methods oftreating insulin resistance in a patient in need thereof, comprising thestep of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In yet other embodiments, the invention is directed to methods ofcausing insulin secretion in a patient, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.        In certain embodiments, the patient suffers from diabetes. In        other embodiments, the patient suffers from abnormal adipocyte        activity. In yet other embodiments, the patient suffers from        insulin resistance. In certain embodiments, the patient suffers        from metabolic syndrome.

In yet other embodiments, the invention is directed to methods ofincreasing insulin level in a patient, wherein said patient does notsuffer from diabetes, comprising the step of:

administering to said patient an effective amount of a peptide or apharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer.

In certain instances, the monomeric, homodimeric, and heterodimericforms of the C-terminal fragments of ADIPOR1 and ADIPOR2 useful in themethods, compositions, dosage forms, and kits of the invention do nothave the exact sequence as described herein, but are present as avariant form. For example, the monomeric, homodimeric, and heterodimericforms of the C-terminal fragments of ADIPOR1 and ADIPOR2 of theinvention can substitute at least about 5%, at least about 10%, or evenat least about 25% of their amino acids without having a loss offunction. Accordingly, at least some of the amino acids in the peptidesof the heterodimers can be substituted with other amino acids.

In certain embodiments of the invention, the monomeric peptide has atleast about 78% identity with SEQ ID NO:1, preferably, the monomericpeptide has at least about 81% identity with SEQ ID NO:1, morepreferably, the monomeric peptide has at least about 84% identity withSEQ ID NO:1, yet even more preferably, the monomeric peptide has atleast about 87% identity with SEQ ID NO:1, even more preferably, themonomeric peptide has at least about 90% identity with SEQ ID NO:1, yeteven more preferably, the monomeric peptide has at least about 93%identity with SEQ ID NO:1, and still more preferably, the monomericpeptide has at least about 96% identity with SEQ ID NO:1.

In certain embodiments of the invention where the peptide is heterodimerof a CTF32, the first mer unit has at least about 78% identity with SEQID NO:1 and the second mer unit has at least about 78% identity with SEQID NO:2, preferably, the first mer unit has at least about 81% identitywith SEQ ID NO:1 and the second mer unit has at least about 81% identitywith SEQ ID NO:2, more preferably, the first mer unit has at least about84% identity with SEQ ID NO:1 and the second mer unit has at least about84% identity with SEQ ID NO:2, yet even more preferably, the first merunit has at least about 87% identity with SEQ ID NO:1 and the second merunit has at least about 87% identity with SEQ ID NO:2, even morepreferably, the first mer unit has at least about 90% identity with SEQID NO:1 and the second mer unit has at least about 90% identity with SEQID NO:2, yet even more preferably, the first mer unit has at least about93% identity with SEQ ID NO:1 and the second mer unit has at least about93% identity with SEQ ID NO:2, and still more preferably, the first merunit has at least about 96% identity with SEQ ID NO:1 and the second merunit has at least about 96% identity with SEQ ID NO:2.

In certain embodiments of the invention where the peptide is homodimerof R1 CTF32, the first mer unit has at least about 78% identity with SEQID NO:1 and the second mer unit has at least about 78% identity with SEQID NO:1, preferably, the first mer unit has at least about 81% identitywith SEQ ID NO:1 and the second mer unit has at least about 81% identitywith SEQ ID NO:1, more preferably, the first mer unit has at least about84% identity with SEQ ID NO:1 and the second mer unit has at least about84% identity with SEQ ID NO:1, yet even more preferably, the first merunit has at least about 87% identity with SEQ ID NO:1 and the second merunit has at least about 87% identity with SEQ ID NO:1, even morepreferably, the first mer unit has at least about 90% identity with SEQID NO:1 and the second mer unit has at least about 90% identity with SEQID NO:1, yet even more preferably, the first mer unit has at least about93% identity with SEQ ID NO:1 and the second mer unit has at least about93% identity with SEQ ID NO:1, and still more preferably, the first merunit has at least about 96% identity with SEQ ID NO:1 and the second merunit has at least about 96% identity with SEQ ID NO:1.

In certain embodiments of the invention where the peptide is homodimerof R2 CTF32, the first mer unit has at least about 78% identity with SEQID NO:2 and the second mer unit has at least about 78% identity with SEQID NO:2, preferably, the first mer unit has at least about 81% identitywith SEQ ID NO:2 and the second mer unit has at least about 81% identitywith SEQ ID NO:2, more preferably, the first mer unit has at least about84% identity with SEQ ID NO:2 and the second mer unit has at least about84% identity with SEQ ID NO:2, yet even more preferably, the first merunit has at least about 87% identity with SEQ ID NO:2 and the second merunit has at least about 87% identity with SEQ ID NO:2, even morepreferably, the first mer unit has at least about 90% identity with SEQID NO:2 and the second mer unit has at least about 90% identity with SEQID NO:2, yet even more preferably, the first mer unit has at least about93% identity with SEQ ID NO:2 and the second mer unit has at least about93% identity with SEQ ID NO:2, and still more preferably, the first merunit has at least about 96% identity with SEQ ID NO:2 and the second merunit has at least about 96% identity with SEQ ID NO:2.

In certain embodiments of the invention where the peptide is heterodimerof a R1 CTF25 and a R2 CTF25, the first mer unit has at least about 80%identity with SEQ ID NO:5 and the second mer unit has at least about 80%identity with SEQ ID NO:6, preferably, the first mer unit has at leastabout 85% identity with SEQ ID NO:5 and the second mer unit has at leastabout 85% identity with SEQ ID NO:6, more preferably, the first mer unithas at least about 90% identity with SEQ ID NO:5 and the second mer unithas at least about 90% identity with SEQ ID NO:6, yet even morepreferably, the first mer unit has at least about 95% identity with SEQID NO:5 and the second mer unit has at least about 95% identity with SEQID NO:6, even more preferably, the first mer unit has at least about 98%identity with SEQ ID NO:5 and the second mer unit has at least about 98%identity with SEQ ID NO:6.

In certain embodiments of the invention where the peptide is homodimerof R1 CTF 25, the first mer unit has at least about 80% identity withSEQ ID NO:5 and the second mer unit has at least about 80% identity withSEQ ID NO:5, preferably, the first mer unit has at least about 85%identity with SEQ ID NO:5 and the second mer unit has at least about 85%identity with SEQ ID NO:5, more preferably, the first mer unit has atleast about 90% identity with SEQ ID NO:5 and the second mer unit has atleast about 90% identity with SEQ ID NO:5, yet even more preferably, thefirst mer unit has at least about 95% identity with SEQ ID NO:5 and thesecond mer unit has at least about 95% identity with SEQ ID NO:5, evenmore preferably, the first mer unit has at least about 98% identity withSEQ ID NO:5 and the second mer unit has at least about 98% identity withSEQ ID NO:5.

In certain embodiments of the invention where the peptide is homodimerof R2 CTF 25, the first mer unit has at least about 80% identity withSEQ ID NO:6 and the second mer unit has at least about 80% identity withSEQ ID NO:6, preferably, the first mer unit has at least about 85%identity with SEQ ID NO:6 and the second mer unit has at least about 85%identity with SEQ ID NO:6, more preferably, the first mer unit has atleast about 90% identity with SEQ ID NO:6 and the second mer unit has atleast about 90% identity with SEQ ID NO:6, yet even more preferably, thefirst mer unit has at least about 95% identity with SEQ ID NO:6 and thesecond mer unit has at least about 95% identity with SEQ ID NO:6, evenmore preferably, the first mer unit has at least about 98% identity withSEQ ID NO:6 and the second mer unit has at least about 98% identity withSEQ ID NO:6.

In certain embodiments of the invention where the peptide is aheterodimer of a R1 CTF25 and a R1 CTF32, the first mer unit has atleast about 80% identity with SEQ ID NO:1 and the second mer unit has atleast about 80% identity with SEQ ID NO:5, preferably, the first merunit has at least about 85% identity with SEQ ID NO:1 and the second merunit has at least about 85% identity with SEQ ID NO:5, more preferably,the first mer unit has at least about 90% identity with SEQ ID NO:1 andthe second mer unit has at least about 90% identity with SEQ ID NO:5,yet even more preferably, the first mer unit has at least about 95%identity with SEQ ID NO:1 and the second mer unit has at least about 95%identity with SEQ ID NO:5, even more preferably, the first mer unit hasat least about 98% identity with SEQ ID NO:1 and the second mer unit hasat least about 98% identity with SEQ ID NO:5.

In certain embodiments of the invention where the peptide is aheterodimer of a R2 CTF25 and a R1 CTF32, the first mer unit has atleast about 80% identity with SEQ ID NO:1 and the second mer unit has atleast about 80% identity with SEQ ID NO:6, preferably, the first merunit has at least about 85% identity with SEQ ID NO:1 and the second merunit has at least about 85% identity with SEQ ID NO:6, more preferably,the first mer unit has at least about 90% identity with SEQ ID NO:1 andthe second mer unit has at least about 90% identity with SEQ ID NO:6,yet even more preferably, the first mer unit has at least about 95%identity with SEQ ID NO:1 and the second mer unit has at least about 95%identity with SEQ ID NO:6, even more preferably, the first mer unit hasat least about 98% identity with SEQ ID NO:1 and the second mer unit hasat least about 98% identity with SEQ ID NO:6.

In certain embodiments of the invention where the peptide is aheterodimer of a R1 CTF25 and a R2 CTF32, the first mer unit has atleast about 80% identity with SEQ ID NO:2 and the second mer unit has atleast about 80% identity with SEQ ID NO:5, preferably, the first merunit has at least about 85% identity with SEQ ID NO:2 and the second merunit has at least about 85% identity with SEQ ID NO:5, more preferably,the first mer unit has at least about 90% identity with SEQ ID NO:2 andthe second mer unit has at least about 90% identity with SEQ ID NO:5,yet even more preferably, the first mer unit has at least about 95%identity with SEQ ID NO:2 and the second mer unit has at least about 95%identity with SEQ ID NO:5, even more preferably, the first mer unit hasat least about 98% identity with SEQ ID NO:2 and the second mer unit hasat least about 98% identity with SEQ ID NO:5.

In certain embodiments of the invention where the peptide is heterodimerof a R2 CTF25 and a R2 CTF32, the first mer unit has at least about 80%identity with SEQ ID NO:2 and the second mer unit has at least about 80%identity with SEQ ID NO:6, preferably, the first mer unit has at leastabout 85% identity with SEQ ID NO:2 and the second mer unit has at leastabout 85% identity with SEQ ID NO:6, more preferably, the first mer unithas at least about 90% identity with SEQ ID NO:2 and the second mer unithas at least about 90% identity with SEQ ID NO:6, yet even morepreferably, the first mer unit has at least about 95% identity with SEQID NO:2 and the second mer unit has at least about 95% identity with SEQID NO:6, even more preferably, the first mer unit has at least about 98%identity with SEQ ID NO:2 and the second mer unit has at least about 98%identity with SEQ ID NO:6.

In certain embodiments, the methods are directed to treating patientssuffering from diabetes. In certain embodiments, the methods aredirected to treating patients suffering from abnormal adipocyteactivity. In certain embodiments, the methods are directed to treatingpatients suffering from insulin resistance. In certain embodiments, themethods are directed to treating patients suffering from metabolicsyndrome.

In certain embodiments of the invention, the peptide orpharmaceutically-acceptable salt thereof is administered via aparenteral route. In certain preferred embodiments, the peptide orpharmaceutically-acceptable salt thereof is administered via injection.In other preferred embodiments, the peptide orpharmaceutically-acceptable salt thereof is administered via infusion.In yet other preferred embodiments, the peptide orpharmaceutically-acceptable salt thereof is administered via inhalation.

In another embodiment, the invention is directed to compositions,comprising:

a peptide or a pharmaceutically-acceptable salt thereof;

wherein said peptide is selected from the group consisting of:

-   -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer; and        at least one pharmaceutically-acceptable carrier.

In further embodiments, the invention is directed to compositions,comprising:

a purified peptide or a pharmaceutically-acceptable salt thereof;

-   -   wherein said peptide is selected from the group consisting of:    -   a monomeric peptide having at least about 75% identity with SEQ        ID NO:2;    -   a first heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a first homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:1, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:2, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a second heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:5 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth homodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:6 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a third heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fourth heterodimer comprising a first mer unit and a second        mer unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:1 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a fifth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:5, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a sixth heterodimer comprising a first mer unit and a second mer        unit, wherein said first mer unit has at least about 75%        identity with SEQ ID NO:2 and wherein said second mer unit has        at least about 75% identity with SEQ ID NO:6, and wherein said        first mer unit and said second mer unit are linked via a        disulfide bond;    -   a dimer of said first heterodimer;    -   a dimer of said first homodimer;    -   a dimer of said second homodimer;    -   a dimer of said second heterodimer;    -   a dimer of said third homodimer;    -   a dimer of said fourth homodimer;    -   a dimer of said third heterodimer;    -   a dimer of said fourth heterodimer;    -   a dimer of said fifth heterodimer; and    -   a dimer of said sixth heterodimer;

optionally, at least one pharmaceutically-acceptable carrier.

In yet other embodiments, the invention is directed to injectable dosageforms, comprising:

the composition described herein; and

at least one solvent for said peptide.

In other embodiments, the invention is directed to inhalable dosageforms, comprising:

the composition described herein; and

at least one pharmaceutically-acceptable carrier for administration ofsaid peptide via inhalation.

In another embodiment, the invention is directed to kits, comprising:

instructions for administering an injectable dosage form to a patient;

a container comprising a composition described herein;

a container comprising a pharmaceutically-acceptable solvent for saidcompositions.

In other embodiments, the invention is directed to kits, comprising:

instructions for administering an inhalable dosage form to a patient;

a container comprising a composition described herein;

a container comprising a pharmaceutically-acceptable solvent for saidcomposition.

In certain embodiments of the invention, the composition is lyophilized.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration, which ispreferably a parenteral route, especially intravenous (via injection orvia infusion) or via inhalation. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol, or other synthetic solvents; antibacterial agents, such asbenzyl alcohol or methyl parabens; antioxidants, such as ascorbic acidor sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid; buffers, such as acetates, citrates, orphosphates, and agents for adjusting tonicity, such as sodium chlorideor dextrose. pH can be adjusted with acids or bases, such ashydrochloric acid or sodium hydroxide. The parenteral preparation can beenclosed in ampoules, disposable syringes, or multiple dose vials madeof glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEM™ (BASF, Parsippany, N.J.) or phosphate-buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, a pharmaceutically-acceptable polyol like glycerol,propylene glycol, liquid polyethylene glycol, and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols, such as mannitol, sorbitol, and sodium chloride inthe composition. Prolonged absorption of the injectable composition canbe brought about by including in the composition an agent that delaysabsorption, for example, aluminum monostearate and gelatin. Sterileinjectable solutions can be prepared by incorporating the activeingredient (i.e., the polypeptide) in the required amount in anappropriate solvent with one or a combination of ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the active compound into asterile vehicle which contains a basic dispersion medium and the otherrequired ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and freeze-drying,which yield a powder of the active ingredient plus and desiredingredients from a previously sterile-filtered solution thereof.

For administration via inhalation, the peptides are delivered in theform of an aerosol spray from a pressurized container or dispenser thatcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

It is especially advantageous to formulate the compositions in dosageunit form for ease of administration and uniformity of dosage. Dosageunit form, as used herein, refers to physically discrete units suited asunitary dosages for the patient to be treated; each unit containing apredetermined quantity of the peptide calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. The specification for the dosage unit forms of the inventionare dictated by and directly dependent on the unique characteristics ofthe active compound and the particular therapeutic effect to beachieved, and the limitations inherent in the art of compounding such anactive compound for the treatment of the patients.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

In certain embodiments of the invention, the compositions furthercomprise at least one pharmaceutically-acceptable carrier. In certainpreferred embodiments, the pharmaceutically-acceptable carrier is sodiumlactate. Other pharmaceutical carriers useful in the solutions andcompositions useful in the practice of the present invention include,but are not limited to, proteins, peptides, amino acids, lipids,polymers, and carbohydrates (e.g., sugars, including monosaccharides,di-, tri-, terra-, and oligosaccharides; derivatized sugars such asalditols, aldonic acids, esterified sugars; and polysaccharides or sugarpolymers), which may be present singly or in combination. Exemplaryprotein carriers include serum albumin such as human serum albumin(HSA), recombinant human albumin (rHA), gelatin, and casein.Representative amino acid/polypeptide components, which may alsofunction in a buffering capacity, include alanine, glycine, arginine,betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine,leucine, proline, isoleucine, valine, methionine, phenylalanine, andaspartame. Polyamino acids of the representative amino acids such asdi-leucine and tri-leucine are also suitable for use with the presentinvention. Carbohydrate carriers suitable for use in the inventioninclude, for example, monosaccharides such as fructose, maltose,galactose, glucose, D-mannose, and sorbose; disaccharides, such aslactose, sucrose, trehalose, cellobiose; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, and starches; andalditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), and myoinositol. Additionally, the solutions andcompositions useful in the invention may include polymeric carriers suchas polyvinylpyrrolidones, hydroxypropyl methylcellulose,methylcellulose, ethylcellulose, Ficolls (a polymeric sugar), dextran,dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-P-cyclodextrin,hydroxyethyl starch), polyethylene glycols, pectin, salts (e.g., sodiumchloride), antioxidants, antistatic agents, surfactants (e.g.,polysorbates such as ‘TWEEN 20” and ‘TWEEN 80”, lecithin, oleic acid,benzalkonium chloride, and sorbitan esters), lipids (e.g.,phospholipids, fatty acids), steroids (e.g., cholesterol), and chelatingagents (e.g., EDTA). Other examples of pharmaceutical carriers and/oradditives suitable for use in the solutions and compositions of theinvention are listed in Remington: The Science & Practice of Pharmacy,20th ed., Williams & Williams, (2000), and in the Physician's DeskReference, 52nd ed., Medical Economics, Montvale, N.J. (1998), thedisclosures of which are herein incorporated by reference.

In certain embodiments of the invention, the pharmaceutically-acceptablesolvent for the peptides of the invention or apharmaceutically-acceptable salt thereof is water, aqueous sodiumchloride solution, aqueous potassium chloride solution, aqueousmagnesium chloride hexahydrate solution, aqueous sodium acetatetrihydrate solution, aqueous sodium gluconate solution, aqueous sodiumhydroxide solution, aqueous dextrose solution, Lactated Ringer'ssolution, or a combination thereof. In certain embodiments of theinvention, the pharmaceutically-acceptable solvent for the peptides ofthe invention or a pharmaceutically-acceptable salt thereof is aqueousalcohol, such as, for example, 20% ethanol.

In certain embodiments of the invention, the solution comprising thepeptides of the invention or a pharmaceutically-acceptable salt thereofhas a pH of about 3.5 to about 5.5. The solution may also include abuffer or a pH adjusting agent; typically, the buffer is a salt preparedfrom an organic acid or base. Representative buffers include organicacid salts such as salts of citric acid, ascorbic acid, gluconic acid,carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalicacid; Tris, tromethamine hydrochloride, or phosphate buffers.

In certain embodiments of the invention, the peptides of the inventionand pharmaceutically-acceptable salts thereof or compositions comprisingthese heterodimers are lyophilized.

The various dosage forms are prepared in accordance with acceptablepharmaceutical procedures, such as described in Remington: The Scienceand Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.; LippincottWilliams & Wilkins: Philadelphia, Pa., (2000).

In addition, the compositions of the invention may further comprise asecond active ingredient in addition to the peptides of the invention orits pharmaceutically acceptable salt, which is useful for the concurrentor synergistic treatment of diabetes, abnormal adipocyte activity, andinsulin resistance. These compounds, and compositions thereof, mayinclude additional compounds known to be useful for the treatment ofdiabetes, abnormal adipocyte activity, and insulin resistance. Suitableadditional compounds include sulfonylureas, meglitinides, biguanides,thiazolidinediones, DPP-4 Inhibitors, alpha-glucosidase inhibitors,glucagons like-peptide (GLP-1)/exendin-4, and combinations thereof.

The peptides of the invention or its pharmaceutically acceptable salt ofthe invention may be prepared in a number of ways well known to thoseskilled in the art. The peptides of the invention and theirpharmaceutically acceptable salts can be synthesized, for example, bythe methods described below, or variations thereon as appreciated by theskilled artisan. All processes disclosed in association with the presentinvention are contemplated to be practiced on any scale, includingmilligram, gram, multigram, kilogram, multikilogram or commercialindustrial scale.

The heterodimers useful in the invention may be prepared recombinantlyor synthesized by conventional methods in liquid-phase or solid-phase,using manual or automated techniques. Suitable methods are describedgenerally, for example, in:

-   Atherton, E. and Sheppard, R. C., Solid Phase peptide synthesis: a    practical approach. Oxford, England: IRL Press (1989);-   Stewart, J. M. and Young, J. D., Solid phase peptide synthesis, 2nd    edition, Rockford: Pierce Chemical Company, 91 (1984);-   R. B. Merrifield, “Solid Phase Peptide Synthesis. I. The Synthesis    of a Tetrapeptide,” J. Am. Chem. Soc. 85 (14): 2149-2154 (1963); and-   L. A. Carpino “1-Hydroxy-7-azabenzotriazole. An efficient peptide    coupling additive,” J. Am. Chem. Soc. 115 (10): 4397-4398 (1993);    which are incorporated herein by reference. Additionally, any    portion of the amino acid sequence of the peptides can be altered    during direct synthesis and/or combined using chemical methods with    sequences with other proteins to produce a variant peptide.

Preferably, the peptides are prepared by conventional solid-phasepeptide synthesis methodology. Standard synthesis protocols based onFmoc chemistry may be used. After synthesis, the crude peptides arecleaved from the solid support and side-chain protecting groups areremoved. The crude peptides can be purified, for example, by preparativehigh performance liquid chromatography, such as C18 reverse-phase HPLC.The purified peptide can be further desalted by HPLC and lyophilized todry form. Preferable, the peptides are stored in sealed containers undernitrogen.

All forms of the peptides of the invention, including free acid, freebase, zwitterionic form, isomorphic crystalline forms, all chiral,enantiomeric, racemic forms, hydrates, solvates, salts and acid salthydrates, are contemplated to be within the scope of the presentinvention. The free acid and the sodium, potassium, and calcium saltsare the preferred forms.

The peptides of the invention may contain one or more asymmetricallysubstituted carbon atoms, and may be isolated in optically active orracemic forms. Thus, all chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Itis well known in the art how to prepare and isolate such opticallyactive forms. For example, mixtures of stereoisomers may be separated bystandard techniques including, but not limited to, resolution of racemicforms, normal, reverse-phase, and chiral chromatography, preferentialsalt formation, recrystallization, and the like, or by chiral synthesiseither from chiral starting materials or by deliberate synthesis oftarget chiral centers.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred protecting groups includethe benzyloxycarbonyl group and the tert-butyloxycarbonyl group. Otherpreferred protecting groups that may be employed in accordance with thepresent invention may be described in Greene, T. W. and Wuts, P. G. M.,Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.

Pharmaceutical kits useful in, for example, the treatment of diabetes,abnormal adipocyte activity, and insulin resistance, which comprise aneffective amount of peptides of the invention orpharmaceutically-acceptable salts thereof in one or more sterilecontainers, are also within the ambit of the present invention.Sterilization of the container may be carried out using conventionalsterilization methodology well known to those skilled in the art. Thesterile containers of materials may comprise separate containers, or oneor more multi-part containers, as exemplified by the UNIVIAL™ two-partcontainer (available from Abbott Labs, Chicago, Ill.), as desired. Suchkits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as for example,additional vials for mixing the components, etc., as will be readilyapparent to those skilled in the art. Instructions, either as inserts oras labels, indicating quantities of the components to be administered,guidelines for administration, and/or guidelines for mixing thecomponents, may also be included in the kit.

The present invention is further defined in the following Examples, inwhich all parts and percentages are by weight, unless otherwise stated.It should be understood that these examples, while indicating preferredembodiments of the invention, are given by way of illustration only.From the above discussion and these examples, one skilled in the art canascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

EXAMPLES Example 1: Synthesis of Monomeric Peptides and Dimeric Peptides

The monomeric peptides (R1 CTF32, R2 CTF32, R1 CTF 30, R1 CTF25, R2 CTF25, R1 CTF18, R2 CTF18, R1 CTF9, R2 CTF9), homodimeric peptides (R1CTF32 R1 CTF32, R2 CTF32 R2 CTF32, R1 CTF25 R1 CTF25, R2 CTF25 R2CTF25), and heterodimeric peptides (R1 CTF32 R2 CTF32, R1 CTF25 R2CTF25) were synthesized using conventional solid-phase peptide synthesismethodology:

Monomeric Peptide Units

SEQ ID NO: 1 (ECM32; RI CTF32): VVAAAFVHFYGVSNLQEFRYGLEGGCTDDTLLSEQ ID NO: 2 (R2 CTF32): VVAGAFVHFHGVSNLQEFRFMIGGGCSEEDALSEQ ID NO: 11 (R1 CTF30): HVLVVAAAFVHFYGVSNLQEFRYGLEGGCTSEQ ID NO: 12 (R2 CTF30): HIFVVAGAFVHFHGVSNLQEFRFMIGGGCSSEQ ID NO: 5 (R1 CTF25): HFYGVSNLQEFRYGLEGGCTDDTLLSEQ ID NO: 6 (R2 CTF25): HFHGVSNLQEFRFMIGGGCSEEDALSEQ ID NO: 7 (R1 CTF18): LQEFRYGLEGGCTDDTLL SEQ ID NO: 8 (R2 CTF18):LQEFRFMIGGGCSEEDAL SEQ ID NO: 9 (R1 CTF9): GGCTDDTLLSEQ ID NO: 10 (R2 CTF9): GGCSEEDAL

Homodimeric Peptides (Monomeric Units are Connected Via a DisulfideLinkage Between the Cysteine in the First Mer Unit and the Cysteine inthe Second Mer Unit)

SEQ ID NO: 1 linked to SEQ ID NO: 1 (R1 CTF32 R1 CTF32):VVAAAFVHFYGVSNLQEFRYGLEGGCTDDTLL                          |VVAAAFVHFYGVSNLQEFRYGLEGGCTDDTLLSEQ ID NO: 2 linked to SEQ ID NO: 2 (R2 CTF32 R2 CTF32):VVAGAFVHFHGVSNLQEFRFMIGGGCSEEDAL                          |VVAGAFVHFHGVSNLQEFRFMIGGGCSEEDALSEQ ID NO: 5 linked to SEQ ID NO: 5 (R1 CTF25 R1 CTF25):HFYGVSNLQEFRYGLEGGCTDDTLL                   | HFYGVSNLQEFRYGLEGGCTDDTLLSEQ ID NO: 6 linked to SEQ ID NO: 6 (R2 CTF25 R2 CTF25):HFHGVSNLQEFRFMIGGGCSEEDAL                   | HFHGVSNLQEFRFMIGGGCSEEDAL

Heterodimeric Peptides (Monomeric Units are Connected Via a DisulfideLinkage Between the Cysteine in the First Mer Unit and the Cysteine inthe Second Mer Unit)

SEQ ID NO: 1 linked to SEQ ID NO: 2 (R1 CTF32 R1 CTF32):VVAAAFVHFYGVSNLQEFRYGLEGGCTDDTLL                          |VVAGAFVHFHGVSNLQEFRFMIGGGCSEEDALSEQ ID NO: 5 linked to SEQ ID NO: 6 (R1 CTF25 R2 CTF25):HFYGVSNLQEFRYGLEGGCTDDTLL                   | HFHGVSNLQEFRFM1GGGCSEEDALSEQ ID NO: 1 linked to SEQ ID NO: 5 (R1 CTF32 R1 CTF25):VVAAAFVHFYGVSNLQEFRYGLEGGCTDDTLL                          |       HFYGVSNLQEFRYGLEGGCTDDTLLSEQ ID NO: 1 linked to SEQ ID NO: 6 (R1 CTF32 R2 CTF25):VVAAAFVHFYGVSNLQEFRYGLEGGCTDDTLL                          |       HFHGVSNLQEFRFM1GGGCSEEDALSEQ ID NO: 2 linked to SEQ ID NO: 5 (R2 CTF32 R1 CTF25):VVAGAFVHFHGVSNLQEFRFMIGGGCSEEDAL                          |       HFYGVSNLQEFRYGLEGGCTDDTLLSEQ ID NO: 2 linked to SEQ ID NO: 6 (R2 CTF32 R2 CTF25):VVAGAFVHFHGVSNLQEFRFMIGGGCSEEDAL                          |       HFHGVSNLQEFRFMIGGGCSEEDAL

Standard synthesis protocols based on Fmoc chemistry were used toprepare the monomeric peptides, which are in turn used to prepare thedimeric peptides. After synthesis, the crude peptides were cleaved fromthe solid support and side-chain protecting groups were removed. Thecrude peptides were purified by C18 reverse-phase HPLC using Varian SD-2Instrument. The peptides were eluted with a gradient of Buffer B for 30minutes (Buffer A: aqueous phase with 0.1% TFA, pH 2.5 and Buffer B:acetonitrile; flow rate 600 ml/min and detection at 230 mm). Thepurified peptide were further desalted by HPLC and lyophilized to dryform. The peptides were characterized by analytical HPLC analysis andmass spectrometry analysis, and then packed in sealed vials filled withnitrogen.

To form the homodimeric or heterodimeric peptides, the appropriatemonomeric peptide is first formed and then thiol groups of the cysteineunits in each monomeric peptide is oxidized to form a disulfide bond.

If there is more than one cysteine in a mer unit, all of the cysteinesmay be oxidized to form thermodynamically stable products by scramblingwith a suitable oxidative reagent in a batch process. Alternatively, ifthere is more than one cysteine in a mer unit, the desired pair ofcysteines (one from the first mer unit and the other from the second merunit) is formed selectively at a time while any other cysteines arestill protected. Suitable oxidative reagents to convert the two thiolsto a disulfide bond include, but are not limited to, oxygen (air),dimethyl sulfoxide, oxidized glutathione, potassium ferricyanide,thallium(III) trifluoroacetate. trans-[Pt(en)₂Cl₂]²⁺ may be used for thequantitative formation of intra-molecular disulfide bonds in peptides[J. Am. Chem. Soc., (2001), 122, 6809-6815].

The dimers of the dimers are formed via an association reaction(hydrogen bonding) between the various mer units of the dimers. Forexample, for a dimer of a heterodimer, there is an association betweenthe R1 CTF mer and the R2 CTF mer that holds the two dimers in apreferred binding orientation. The association reaction occurs naturallyin plasma at physiological pH conditions. The dimers of the dimers maybe formed by adjusting the pH of the solution to physiological blood pHconditions, i.e., at about pH 7.4.

Example 2: Proof of Heterodimer

The presence of heterodimer R1 CTF32 R2 CTF32 (SEQ ID NO:1 linked to SEQID NO:2) in clinical samples was determined using ELISA testing withantibodies specific for either R1 CTF32 (SEQ ID NO:1) or R2 CTF32 (SEQID NO:2). ELISA plates were coated with monoclonal antibody for R1 CTF25(SEQ ID NO:5). This monoclonal antibody does not capture the R2 CTF32(SEQ ID NO:2). The analyte bound was detected with a second polyclonalantibody. This experiment was done twice; once with a polyclonalantibody that detected the R1 CTF32 (SEQ ID NO:1) and another time witha polyclonal antibody that detected the R2 CTF32 (SEQ ID NO:2). Neitherantibody cross-reacted with the other receptor fragment.

Example 3: Inhibition of Enzymes

Inhibition of insulin degradation enzyme (IDE) is a biological functionof CTF. The inhibition reduces insulin degradation in the liver andother tissues and thereby increases insulin levels in the blood. Theenzymes for cleavage of the dimers are also potential therapeutictargets. Each of the peptides synthesized in Example 1 was tested fortheir effect on cleavage and target enzymes (ADAM-17 and IDE at level of400 ng/ml). The results are shown in TABLE 2 below:

TABLE 2 ADAM-17 IDE Inhibition Inhibition (90% Units Description(observed) inhibition at) Monomer R1 CTF30 Negative Negative Monomer R1CTF32 Positive 50.0 μg/ml Monomer R1 CTF25 Negative 12.4 μg/ml MonomerR1 CTF17 Negative negative Monomer R1 CTF9 Negative negative Monomer R2CTF32 Positive 40.0 μg/ml Monomer R2 CTF25 Negative 9.0 μg/ml Monomer R2CTF9 Negative Negative Homodimer R1 CTF32 R1 CTF32 Positive 22.5 μg/mlHomodimer R2 CTF32 R2 CTF32 Positive 19.0 μg/ml Heterodimer R1 CTF32 R2CTF32 Positive 1.2 μg/ml Heterodimer R1 CTF25 R2 CTF25 Negative 0.6μg/ml

The data in TABLE 2 shows that the homodimers and heterodimers of CTFinhibit ADAM-17 and inhibit IDE. The data further shows that theheterodimer (R1 CTF32 R2 CTF32) was more active than the correspondinghomodimers (R1 CTF32 R1 CTF32 and R2 CTF32 R2 CTF32). This is unexpectedbecause the homology between R1 CTF32 and R2 CTF32 is very high and nolarge reactivity differences were observed between R1 CTF32 and R2CTF32), with the data for the effect of IDE activity and TACE activityfor R2 CTF32 shown in FIG. 1 and FIG. 2.

Example 4: Testing of Diabetic Patients

The assay for R1 CTF32 (SEQ ID NO:1) using the R1 CTF 32 monoclonalantibody and the R1 CTF32 polyclonal antibody described in Example 2 wasused to determine plasma levels of R1 in diabetic and normal patients.This assay detects any forms of R1 forms whether monomeric, dimeric, orbound. The results are shown in FIG. 3.

The assay for R1 CTF32 R2 CTF32 (SEQ ID NO:1 linked to SEQ ID NO:2)using the R1 CTF 32 monoclonal antibody and the R2 CTF32 polyclonalantibody described in Example 2 was used to determine plasma levels ofheterodimeric R1 CTF32 R2 CTF32 in diabetic and normal patients. Thisassay does not detect monomeric form and would only detect heterodimericform. Filtering of the samples to remove other proteins binding theheterodimeric R1 CTF32 R2 CTF32 did not impact the results. The resultsare shown in FIG. 4.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations, and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A method for determining progression, onset, or efficacy of treatmentof Alzheimer's disease in a patient, comprising: determining a level ofa peptide in a biological fluid sample obtained from said patient;wherein said peptide is a heterodimer comprising a first mer unit and asecond mer unit, wherein said first mer unit consists of 25 amino acidsand has at least about 75% identity with SEQ ID NO:5 and wherein saidsecond mer unit consists of 25 amino acids and has at least about 75%identity with SEQ ID NO:6, and wherein said first mer unit and saidsecond mer unit are linked via a disulfide bond; a first homodimercomprising a first mer unit and a second mer unit, wherein said firstmer unit consists of 25 amino acids and has at least about 75% identitywith SEQ ID NO:5 and wherein said second mer unit consists of 25 aminoacids and has at least about 75% identity with SEQ ID NO:5, and whereinsaid first mer unit and said second mer unit are linked via a disulfidebond; a second homodimer comprising a first mer unit and a second merunit, wherein said first mer unit consists of 25 amino acids and has atleast about 75% identity with SEQ ID NO:6 and wherein said second merunit consists of 25 amino acids and has at least about 75% identity withSEQ ID NO:6, and wherein said first mer unit and said second mer unitare linked via a disulfide bond; a dimer of said heterodimer; a dimer ofsaid first homodimer; or a dimer of said second homodimer; andcorrelating the level of said heterodimer, said homodimer, or said dimerwith said progression, onset, or efficacy of treatment of Alzheimer'sdisease.
 2. The method of claim 1, wherein said level of peptide isdetermined using an immunoassay. 3.-15. (canceled)
 16. A method ofinhibiting insulin degradation enzyme (IDE) in a patient suffering fromAlzheimer's disease, comprising: administering to said patient aneffective amount of a peptide or a pharmaceutically-acceptable saltthereof; wherein said peptide is a heterodimer comprising a first merunit and a second mer unit, wherein said first mer unit consists of 25amino acids and has at least about 75% identity with SEQ ID NO:5 andwherein said second mer unit consists of 25 amino acids and has at leastabout 75% identity with SEQ ID NO:6, and wherein said first mer unit andsaid second mer unit are linked via a disulfide bond; a first homodimercomprising a first mer unit and a second mer unit, wherein said firstmer unit consists of 25 amino acids and has at least about 75% identitywith SEQ ID NO:5 and wherein said second mer unit consists of 25 aminoacids and has at least about 75% identity with SEQ ID NO:5, and whereinsaid first mer unit and said second mer unit are linked via a disulfidebond; a second homodimer comprising a first mer unit and a second merunit, wherein said first mer unit consists of 25 amino acids and has atleast about 75% identity with SEQ ID NO:6 and wherein said second merunit consists of 25 amino acids and has at least about 75% identity withSEQ ID NO:6, and wherein said first mer unit and said second mer unitare linked via a disulfide bond; a dimer of said heterodimer, a dimer ofsaid first homodimer, or a dimer of said second homodimer. 17.(canceled)
 18. (canceled)
 19. A method of treating Alzheimer's diseasein a patient, comprising: administering to said patient an effectiveamount of a peptide or a pharmaceutically-acceptable salt thereof;wherein said peptide is a heterodimer comprising a first mer unit and asecond mer unit, wherein said first mer unit consists of 25 amino acidsand has at least about 75% identity with SEQ ID NO:5 and wherein saidsecond mer unit consists of 25 amino acids and has at least about 75%identity with SEQ ID NO:6, and wherein said first mer unit and saidsecond mer unit are linked via a disulfide bond; a first homodimercomprising a first mer unit and a second mer unit, wherein said firstmer unit consists of 25 amino acids and has at least about 75% identitywith SEQ ID NO:5 and wherein said second mer unit consists of 25 aminoacids and has at least about 75% identity with SEQ ID NO:5, and whereinsaid first mer unit and said second mer unit are linked via a disulfidebond; a second homodimer comprising a first mer unit and a second merunit, wherein said first mer unit consists of 25 amino acids and has atleast about 75% identity with SEQ ID NO:6 and wherein said second merunit consists of 25 amino acids and has at least about 75% identity withSEQ ID NO:6, and wherein said first mer unit and said second mer unitare linked via a disulfide bond; a dimer of said heterodimer; a dimer ofsaid first homodimer; or a dimer of said second homodimer. 20.-44.(canceled)